UNIT 2: Clinical Trial Phases and Study Types

Definition

Clinical trials involving new drugs are commonly classified into different phases, each phase of the drug approval process being treated as a separate clinical trial.

The phased approach allows systematic evaluation of a drug, beginning with early human exposure and progressing toward large-scale confirmation of safety and efficacy. Each phase has a distinct scientific objective and is conducted only after satisfactory outcomes from the previous phase.

Parameter	Phase 0 (Exploratory)	Phase I (Safety)	Phase II (Efficacy & Dose‑Finding)	Phase III (Confirmation)	Phase IV (Post‑Marketing)
Common Synonyms	Micro-dosing studies; Exploratory IND	First-in-Human (FIH); Safety/Tolerability	Therapeutic Exploratory	Therapeutic Confirmatory; Pivotal Trials	Post-Marketing Surveillance (PMS)
Primary Purpose	Characterize PK/PD and target engagement at sub-therapeutic doses	Assess safety, tolerability, PK/PD; define MTD and DLT	Evaluate preliminary efficacy; refine/optimize dose and regimen	Confirm efficacy and safety vs placebo/standard of care in large population	Monitor long-term safety, effectiveness, rare/late adverse events
Typical Sample Size	10–15	20–80	100–300	1,000–3,000	Thousands to millions (real-world scale)
Subjects	Healthy volunteers (sometimes patients in special cases)	Healthy volunteers (patients common in oncology/advanced therapies)	Patients with target disease/condition	Patients with target disease/condition; diverse, multi-center	Real-world patients after approval
Dose Characteristics	Sub-therapeutic micro-doses (≤1/100th of pharmacologically active dose)	Single and multiple ascending doses (SAD/MAD) to define exposure limits	Therapeutic dose range; dose-response exploration (including IIa/IIb)	Final therapeutic dose(s) intended for labeling	Marketed dose(s); routine clinical use
Primary Outcome	PK (Cmax, AUC), PD markers, target engagement, bioavailability	Safety/tolerability, PK/PD, MTD, DLT, recommended Phase II dose (RP2D)	Efficacy signal (clinical endpoints/surrogates), dose-response, RP3D	Statistically robust efficacy and safety vs control; risk–benefit confirmation	Rare AEs, long-term safety/effectiveness, interactions
Secondary Outcome	Preliminary mechanism, metabolism, distribution	Early pharmacodynamic/efficacy signals, immunogenicity (biologics)	Expanded safety profile, QoL, biomarker validation	Quality of life, subgroup analyses, comparative effectiveness	Cost-effectiveness, adherence, real-world performance, pharmacoepidemiology
Design Type	Open-label, exploratory, very small cohorts	Open-label dose-escalation (SAD/MAD), sentinel dosing; sometimes randomized parts	Randomized controlled (placebo/active), parallel-group; adaptive designs common	Large, randomized, double-blind, multi-center, event-driven	Observational studies, registries, pragmatic trials, PASS/PAES
Duration	Days to weeks	Months	1–2 years (varies by disease/endpoint)	2–4 years (or more for outcomes trials)	Ongoing throughout product lifecycle
Regulatory Objective	Feasibility for Phase I; inform human dosing strategy	Define safe starting/upper doses and schedule	Establish proof-of-concept and dose to take into Phase III	Provide substantial evidence for approval (NDA/BLA/MAA)	Fulfill risk management/commitments; refine labeling
Go / No-Go Criteria	Adequate exposure, predictable PK, evidence of target engagement	Acceptable safety/tolerability; defined RP2D	Clinically meaningful efficacy signal and safety at intended dose	Positive, clinically meaningful benefit–risk across populations	Acceptable real-world safety; manageable risks
Blinding	None (typically)	Rare; often open-label early, may include blinded parts later	Often double-blind	Double-blind preferred/standard	Usually open-label; some blinded pragmatic trials exist
Control Used	Usually none	Usually none (may use intra-subject comparisons)	Placebo or active comparator	Placebo and/or active comparator (standard of care)	No control (observational); sometimes external/RWE comparators
Probability of Success (Typical, Approx.)	≈60% progress to Phase I	≈70% progress to Phase II	≈33% progress to Phase III	≈25% receive approval	Not applicable (post-approval)
Cost Range	Low	Medium	High	Very high	Low–Medium (distributed over time)
Key Documents/Outputs	Exploratory study report, PK/PD summary	Investigator’s Brochure updates; RP2D rationale	Proof-of-concept report; dose-selection justification	Pivotal CSR(s); ISE/ISS; submission dossier	Periodic safety reports (PSUR/PBRER); RMP/REMS updates
Ethical Considerations	Minimize exposure risk at sub-therapeutic dosing	Risk mitigation via sentinel cohorts and stopping rules	Equipoise; patient benefit vs uncertainty	Global equity, subgroup representation, DSMB oversight	Real-world consent, data privacy, signal detection
Data Monitoring	Internal review	Safety review committees; stopping rules	Data Safety Monitoring Board (often)	Independent DSMB standard	Pharmacovigilance systems, signal detection algorithms
Statistical Features	Descriptive PK/PD	Descriptive safety; exposure-response exploration	Powered for signal detection; multiplicity control in dose-finding	Confirmatory hypothesis testing; pre-specified endpoints/hierarchy	Observational statistics; time-to-event, disproportionality analyses
Typical Endpoints Examples	Cmax, AUC, half-life, receptor occupancy	TEAE/SAE rates, DLT incidence, PK parameters	Response rate, surrogate biomarkers, PROs	Primary clinical outcomes (e.g., MACE, PFS/OS, exacerbation rate)	Incidence of rare AEs, adherence, health economics outcomes
Sub-Phases / Notable Splits	N/A	SAD vs MAD; food-effect sub-studies	Phase IIa (exploratory) vs IIb (dose-ranging/confirmatory)	Phase IIIa (pre-approval) vs IIIb (label expansion, pre-launch)	PASS/PAES; Risk minimization studies; registries
Randomization	None	Sometimes in later parts	Common	Standard	Rare (mostly observational)
Geographic Scope	Single-center	Single- to few-center	Multi-center, sometimes multinational	Large multi-national programs	Global, routine-care settings
Operational Notes	Ultra-rapid, small cohorts; limited sites	Cautious dose escalation; intensive PK sampling	Adaptive designs common; enrichment strategies	Complex supply, large site networks; rigorous QC	EHR-based data, claims databases, registries
Regulatory Interactions	Pre-IND/Scientific advice (optional)	Safety updates to regulators; IB amendments	End-of-Phase II meetings to align on Phase III	Pre-NDA/BLA meetings; rolling submissions	Post-marketing commitments/variations
Examples of Decision Tools	Microtracer studies; PET occupancy	3+3, mTPI, CRM dose-escalation models	Seamless Phase II/III, Bayesian adaptive designs	Event-driven analyses; interim analyses with alpha-spending	Disproportionality (ROR/PRR), observed vs expected analyses
Patient Involvement	Minimal (volunteer focus)	Safety-centric consent, intensive visits	Patient-reported outcomes gain prominence	QoL and patient-centered endpoints key	Real-world adherence, patient registries, PROs at scale
Typical Timeline Milestones	Protocol → dosing → PK/PD readout	Sentinel dosing → cohort escalations → RP2D	Interim futility/efficacy → final POC	Interims (if any) → primary readout → submission	Safety signal reviews → label updates
Risk Management	Very low dose to limit risk	Stopping rules and sentinel cohorts	Adaptive futility to avoid exposure	DSMB oversight; predefined stopping boundaries	REMS/RMP; ongoing signal detection and mitigation

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Classification of Clinical Trial Phases

Definition

Phase 0 Clinical Trials (Exploratory Studies)

Phase I Clinical Trials: Safety and Tolerability

Phase II Clinical Trials: Dose Finding and Proof of Concept

Phase III Clinical Trials: Confirmatory Studies

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Phase IV Clinical Trials: Post-Marketing Research

Prevention, Screening, and Diagnostic Trials

Treatment Trials

Interventional and Observational Studies

Special Trial Designs and Applications

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